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Biomedical subjects

L P Hackett

Publications and source records attributed to L P Hackett.

At least 37 records · Page 2Linked to original sources
PubMed1996

Enzyme-multiplied immunoassay (EMIT 2000) digoxin assay compared with fluorescence polarization immunoassay and amerlex 125I-radioimmunoassay at two Australian centers.

Digoxin assays in plasma from patients treated with the drug have played an integral role in its therapeutic management. Commercial digoxin immunoassays have been criticized for poor performance owing to various interferences and limited sensitivity. The present study compared the performance of a new enzyme-multiplied immunoassay technique (EMIT 2000) to fluorescence polarization immunoassay (FPIA) and radioimmunoassay (RIA) in two separate Australian centers. Comparisons were made using standard indices of precision and accuracy, samples taken from patients, quality-assurance samples, and cord blood samples from neonates, in which high concentrations of digoxin-like immunoreactive substances (DLIS) would be anticipated. The results confirmed satisfactory precision and accuracy for therapeutic drug monitoring purposes, a sensitivity of < 0.1 microgram/L, and very low DLIS interference, as assessed by assay of neonatal cord blood samples.

Anti-Arrhythmia Agents↗
PubMed1996

Distribution and excretion of sumatriptan in human milk.

1. The excretion of a 6 mg subcutaneous dose of sumatriptan in breast milk was studied in five lactating volunteer subjects with a mean age of 27.6 years and a mean body weight of 75 kg. Drug concentrations in milk and plasma over the ensuing 8 h were measured by high-performance liquid chromatography. 2. The mean milk:plasma ratio estimated from the areas under the milk and plasma concentration-time curves (AUC) was 4.9 (95% CI 4.1-5.7), indicating a significant transfer of sumatriptan into the milk compartment. 3. The mean total recovery of drug in milk was estimated to be only 14.4 micrograms (95% CI 6.1-22.7 micrograms), or 0.24% of the 6 mg administered dose. On a weight-adjusted basis this corresponded to a mean infant exposure of 3.5% of the maternal dose (95% CI 0.3-6.7%). 4. If oral bioavailability in the infant is similar to that in adults (14%), the weight-adjusted infant dose is reduced to 0.49%. Furthermore, allowance for reduced clearance in the infant predicts an infant exposure varying from 4.9% in a very premature neonate to 0.7% in a 30 week old infant. 5. Since sumatriptan is usually administered as a single dose at infrequent intervals, the low level of excretion in breast milk suggests that continued breast feeding following its use will not pose a significant risk to the suckling infant. Even this minor exposure could be largely avoided by expressing and discarding all milk for 8 h after the dose.

Adult↗
PubMed1995

Antidepressant toxicity and the need for identification and concentration monitoring in overdose.

Antidepressant drugs are among the most commonly encountered causes of self-poisoning. These drugs include tricyclics, tetracyclics, bicyclics and monocyclics, as well as monoamine oxidase (MAO) inhibitors and selective serotonin reuptake inhibitors (SSRIs). Of these, the tricyclic antidepressants (TCAs) are generally more toxic in overdose, with major toxicity usually manifesting within the first 6 hours after overdose. Various studies indicate that patients at risk of toxicity from TCA overdose may be identified by neurological, cardiovascular and electrocardiography status, together with a quantitative estimate of the plasma drug concentration. While there are various methods available for such chemical estimations, the most satisfactory appears to be fluorescence polarisation immunoassay which gives rapid quantitative results for a variety of TCAs. The selective MAO-A inhibitor antidepressants and the SSRIs are relatively nontoxic when taken alone. However, overdoses of combinations of MAO inhibitors and either SSRIs or TCAs with serotonin reuptake blocking activity may result in a serotonin syndrome with a severe or fatal outcome. Features of this syndrome include hyperpyrexia, disseminated intravascular coagulation, convulsions, coma and muscle rigidity, which may not develop until 6 to 12 hours after overdose. While quantitative chemical identification of these drugs following overdose is helpful in confirming the diagnosis, it is not mandatory. The increasing use of MAO-A inhibitors and SSRIs in the treatment of depression suggests that careful clinical observation is required when combination overdoses are suspected.

Antidepressive Agents↗
PubMed1993

Patterns of drug use by participants in the Western Australian methadone program, 1984-1991.

OBJECTIVES: To establish the extent to which participants in the WA methadone treatment program used opiates, cannabinoids, benzodiazepines, cocaine and amphetamines, and to define the pattern of such use over time. In addition, the relationships between methadone daily dose and the use of the various drug groups was examined. DESIGN: A retrospective analysis of data from 1678 samples from urinalysis screening over 13 separate surveys between 1984 and 1991. A mean of 35.9% of patients in the program was sampled on each occasion with each patient contributing only one sample in any one survey. Analytical techniques used included enzyme-multiplied immunoassay, thin-layer chromatography and gas chromatography-mass spectrometry. RESULTS: Methadone and/or its major metabolite were detected in most urine samples, indicating satisfactory compliance by patients. The detection of opiates increased from a mean of 27.1% of samples in 1984-1989 to a mean of 44.2% of samples in 1990-1991. Codeine or morphine were most frequently detected (94% of all opiate-positive samples) and were found together in 38.2% of opiate-positive samples. Detection of cannabinoids also increased from a mean of 45.2% of all samples during 1984-1987 to a mean of 56.4% of samples during 1990-1991. Benzodiazepines were found in a mean of 26.7% of samples but use was not time-related. Detection of amphetamine-class drugs doubled from a mean of 8.3% of all samples (mid 1989 to mid 1990) to 16.8% of samples (mid 1990 to mid 1991). The major representatives of the latter group were methylamphetamine (47.3% of amphetamine-positive urines), amphetamine (15.7%) and ephedrine/pseudoephedrine (44.6%). Opiate use was significantly lower (P < 0.05) in those patients taking more than 80 mg methadone/day. In addition, benzodiazepine use increased significantly (P < 0.05) with increasing methadone daily dose. There was no relationship between methadone daily dose and use of cannabinoids or amphetamines. CONCLUSIONS: The increase in the use of opiates, cannabinoids and amphetamines over the period 1984-1991 occurred about four years after the adoption of a harm minimisation treatment philosophy by the WA methadone program. The high prevalence of codeine and morphine in opiate-positive urine samples strongly suggested the use of "home-bake" heroin. In addition, the data showed that methylamphetamine and ephedrine/pseudoephedrine were the most frequently used psychostimulants. Suppression of opiate use in those clients receiving more than 80 mg methadone/day was consistent with earlier studies. However, the significant increase in use of benzodiazepines with increasing methadone daily dose requires further study.

Adult↗
PubMed1993

Plasma concentrations of dothiepin and its metabolites are not correlated with clinical efficacy in major depressive illness.

Plasma concentration-antidepressant response relationships for dothiepin, nordothiepin, dothiepin-S-oxide, and nordothiepin-S-oxide were investigated in 50 patients (33 women and 17 men), who had had a major depressive episode. Depression and anxiety were assessed at the start of therapy and after 2 and 4 weeks by measurement of a Hamilton rating score for depression (HRSD), a Beck depression inventory (BECK), visual analog scores for depression (VASDEP) and anxiety (VASANX), and a physician's global (GLOBAL) score. There were significant (p < 0.001) decreases in both mean depression (32-69%) and mean anxiety (30-44%) scores at weeks 2 and 4, but there were no robust linear or polynomial correlations between percent decrease in depression or anxiety scores and plasma concentrations of dothiepin or its metabolites at week 4. It is suggested that measurement of the nordothiepin/dothiepin ratio may assist in the assessment of compliance.

Adult↗
PubMed1993

Excretion of lignocaine and its metabolite monoethylglycinexylidide in breast milk following its use in a dental procedure. A case report.

The excretion of lignocaine in breast milk has been documented in a 34-year-old woman following the injection of 20 mg lignocaine for a dental alloy restoration in the right upper quadrant. Lignocaine and its primary metabolite monoethylglycinexylidide in milk and plasma were quantified by high-performance liquid chromatography. The concentration of lignocaine in milk ranged from 44-66 micrograms l-1 while that for monoethylglycinexylidide ranged from 35-41 micrograms l-1. The milk: plasma ratios for lignocaine and monoethylglycinexylidide were 1.1 and 1.8, respectively. The calculated daily infant doses for the parent drug and metabolite were both less than 0.01 mg kg-1 day-1. With the exception of very rare allergic reactions, these levels of infant exposure are extremely low and of no toxicological significance. Nursing mothers receiving lignocaine for standard dental procedures can be advised that continuation of breast feeding is safe.

Adult↗
PubMed1992

Comparison of cyclosporine measurement in whole blood by high-performance liquid chromatography, monoclonal fluorescence polarization immunoassay, and monoclonal enzyme-multiplied immunoassay.

Monitoring of cyclosporine concentrations in whole blood is used routinely as a guide to adjusting dose so as to achieve optimal therapeutic benefit with minimal adverse effects. In the present study, we have compared a specific high-performance liquid chromatography (HPLC) assay with a fluorescence polarization immunoassay (TDx) and an enzyme-multiplied immunoassay (Emit). Both Emit and TDx assays employ a monoclonal antibody to cyclosporin A and therefore have the potential for a high degree of specificity. Blood specimens (EDTA as anticoagulant) were obtained from 113 patients (71 renal transplants, 17 liver transplants, and 25 other categories) taking cyclosporine and analysed by all three methods. There were significant correlations between results for HPLC and Emit (Emit = 10.54 + 1.07 x HPLC; r2 = 0.82, p less than 0.001) and between results for HPLC and TDx (TDx = 9.16 + 1.42 x HPLC; r2 = 0.82, p less than 0.001). Compared to HPLC analysis, 74% and 96%, respectively, of Emit and TDx results were to the left of the line of identity. The TDx monoclonal antibody appears to have a lesser degree of specificity than that used in the Emit assay. Mean concentrations of cyclosporine measured by Emit and TDx were 17% and 51% higher, respectively, than those measured by HPLC. Because of this overestimation, we suggest that both Emit and TDx methods may find their most appropriate use in routine therapeutic monitoring of renal transplant patients in whom metabolite concentrations are less variable over time.

Antibodies, Monoclonal↗
PubMed1992

The excretion of dothiepin and its primary metabolites in breast milk.

1. The excretion of dothiepin, nordothiepin, dothiepin-S-oxide and nordothiepin-S-oxide into breast milk was studied in eight women. Exposure to drug was measured in five of their infants, and possible drug-related effects were assessed in all eight infants. 2. Using pre-feed milk samples mean (+/- s.e. mean) milk:plasma (M:P) ratios were 0.78 +/- 0.12, 0.85 +/- 0.16, 1.18 +/- 0.29 and 1.86 +/- 0.29 for dothiepin, nordothiepin, dothiepin-S-oxide and nordothiepin-S-oxide, respectively. In post-feed milk samples, the mean M:P ratio for dothiepin (1.59 +/- 0.32) was significantly greater (P less than 0.05) but M:P ratios for the metabolites were similar. 3. Mean total calculated infant daily doses, (in dothiepin equivalents and as a percent of the maternal dose) were 0.58% for dothiepin, 0.23% for nordothiepin, 2.47% for dothiepin-S-oxide, and 1.17% for nordothiepin-S-oxide. 4. Plasma samples were obtained from five infants. In one, both dothiepin and nordothiepin were below their minimum quantifiable levels (2 micrograms l-1) while in four others both dothiepin-S-oxide and nordothiepin-S-oxide were below their minimum quantifiable levels (10 micrograms l-1). No adverse effects were found in any of the eight infants. 5. Use of dothiepin by depressed mothers is unlikely to be a significant hazard to their breast-feeding infants.

Adult↗
PubMed1991

Disposition of dothiepin after overdose: effects of repeated-dose activated charcoal.

Although the tricyclic antidepressant dothiepin is often encountered in deliberate self-poisonings, there are no published studies of its disposition in overdose. In the present study, we have documented the plasma disposition of dothiepin and its major metabolites in eight overdose patients. All had high initial levels of dothiepin (819-3,851 micrograms/L), dothiepin-S-oxide (655-2,162 micrograms/L), nordothiepin (88-422 micrograms/L), and nordothiepin-S-oxide (176-530 micrograms/L) that were considerably above steady-state therapeutic concentrations. In three patients who received treatment with repeated-dose activated charcoal, dothiepin half-lives were 10.6, 12.5, and 13.1 h compared with the literature range of 18.5-24 h. All patients survived and none experienced any significant cardiovascular event despite exhibiting clinical signs of tricyclic antidepressant overdose. We suggest that repeated-dose activated charcoal treatment may decrease the dothiepin half-life after overdose.

Adult↗
PubMed1991

Excretion of indomethacin in breast milk.

1. The excretion of indomethacin into breast milk and subsequent exposure of infants was studied in 16 women and seven of their infants. The median milk:plasma ratio in seven patients where there were measurable drug concentrations in both milk and plasma was 0.37. 2. Total infant dose, assuming a daily milk intake of 150 ml kg-1 and 100% absorption, ranged from 0.07% to 0.98% (median = 0.18%) of the weight adjusted maternal dose. 3. Plasma samples were obtained in seven infants. In six of these, indomethacin concentrations were below the sensitivity of the assay (less than 20 micrograms l-1), while one infant had a plasma indomethacin concentration of 47 micrograms l-1. 4. No adverse effects due to indomethacin were reported in the infants.

Adult↗
PubMed1987

Simultaneous determination of clobazam, N-desmethyl clobazam and clonazepam in plasma by high performance liquid chromatography.

A method is described for the simultaneous determination of clobazam, its active metabolite N-desmethylclobazam, and clonazepam in plasma by high performance liquid chromatography. The drugs are extracted with diethyl ether from 1.0 ml plasma adjusted to pH 9.0 and separated on a C18 reverse phase column using a mobile phase of 40% acetonitrile in phosphate buffer pH 3.0. The ultraviolet absorbance is monitored at a wavelength of 313 nm. The method has a coefficient of variation of less than 5% and an overall recovery of greater than 85% and is sufficiently sensitive for the therapeutic monitoring of these drugs.

Anti-Anxiety Agents↗
PubMed1987

High-performance liquid chromatographic method for measurement of pentamidine in plasma and its application in an immunosuppressed patient with renal dysfunction.

A rapid method for the quantitation of pentamidine in plasma by high-performance liquid chromatography is described. Pentamidine was extracted from plasma using a mixed solvent of 40% acetonitrile in chloroform. Reversed-phase chromatography was then performed on a mu Bondapak C-18 column, using a mobile phase of acetonitrile containing 0.1% H3PO4 and 0.1% NaCl (20:80) and the eluting peaks detected by their UV absorbance at 262 nm. The assay had a within-day coefficient of variation of less than 3.8%, an absolute recovery of 92%, and a limit of detection of 15 nmol/L. The method was applied during pentamidine mesylate treatment (4 mg/kg/day) for Pneumocystis carinii pneumonia in an immunosuppressed patient with impaired renal function. Plasma levels rose slowly to a plateau (range 530-880 nmol/L) after 7 days of treatment, suggesting a half-life of around 1.5-2 days.

Amidines↗
PubMed1986

The effect of intra-articular steroids on plasma salicylate concentrations.

Plasma salicylate concentrations and salicylate clearances were evaluated in 10 patients before and then 3 days after the intra-articular administration of glucocorticoid steroids. All patients were on chronic salicylate treatment, the dosage varying from 1.3-4.6 g day-1 of enteric-coated aspirin. The mean steady state plasma concentration (+/- s.e. mean) of salicylate decreased significantly after intra-articular steroid (90.9 +/- 14.8 mg l-1-64.7 +/- 8.9, P less than 0.05), whilst the mean clearance increased significantly (87.3 +/- 20.6 ml min-1-120.6 +/- 28.3, P less than 0.05). In these paired studies, the intra-articular administration of steroids lead to a significant decrease in plasma salicylate levels in patients taking enteric-coated aspirin.

Administration, Oral↗